Document Type
Article
Publication Date
2-4-2026
Original Citation
Lindsay H,
Du Y,
Qi L,
Zhang H,
Zhao S,
Braun F,
Kogiso M,
Stephan C,
Alton G,
Stein G,
Beaton G,
Kesari S,
Neuhauser S,
Stearns T,
Chuang J,
Jocoy E,
Bult C,
Teicher B,
Smith M,
Li X.
Targeting Pediatric Glioblastomas by Combining OLIG2 Inhibitor CT-179 with Fractionated Radiation in a Panel of Patient-Derived Orthotopic Xenograft Mouse Models. Int J Mol Sci. 2026;27(3).
Keywords
JMG, Animals, Oligodendrocyte Transcription Factor 2, Humans, Glioblastoma, Mice, Xenograft Model Antitumor Assays, Brain Neoplasms, Child, Cell Line, Tumor, Female, Male, Cell Survival, Disease Models, Animal, Dose Fractionation, Radiation
JAX Source
Int J Mol Sci. 2026;27(3).
ISSN
1422-0067
PMID
41683962
DOI
https://doi.org/10.3390/ijms27031543
Grant
This study was funded by NIH/NCI grants U01 CA217613 (Li XN) and 2UO1 CA199288-06 (LI XN), U24CA263963 (Bult CJ).
Abstract
The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined at 15–240 mg/kg (oral) alone or combined with XRT (2 Gy/day × 5 days). Changes in animal survival times were analyzed using the Kaplan–Meier method, followed by pair-wise comparisons. Increased OLIG2 mRNA expression was detected in seven out of ten PDOX models. CT-179 inhibited cell viability in a time- and dose-dependent manner in all eight pGBM xenograft tumors (IC50 0.03–10 µM) and was potentiated by XRT (0.03–1 µM). Oral gavage (24 mg/kg) of CT-179 for 5 days led to effective penetration in mouse cerebrum (3232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ± 309 ng/g), and PDOX tumors (1814 ± 110.3 ng/g) vs. 361.3 ± 1.5 ng/mL in serum. CT-179 alone was not active at 200 mg/kg in four models, although it was moderately effective at 240 mg/kg in one model. When combined with XRT, a significant extension of animal survival times was observed in two out of four models. Doses needed to eliminate OLIG2 expression in vitro varied from 0.3 to >1 µM in pGBM cells. In summary, our data showed that orally administered CT-179 penetrated the blood–brain barrier (BBB) and exhibited potential for inhibiting pGBM growth when combined with XRT.
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